The Effectiveness of Zinc Supplementation in Taste Disorder Treatment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction Food taste and flavour affect food choice and acceptance, which are essential to maintain good health and quality of life. Reduced circulating zinc levels have been shown to adversely affect the taste, but the efficacy of zinc supplementation to treat disorders of taste remains unclear. In this systematic review and meta-analysis, we aimed to examine the efficacy of zinc supplementation in the treatment of taste disorders. Methods We searched four electronic bibliographical databases: Ovid MEDLINE, Ovid Embase, Ovid AMAD, and PubMed. Article bibliographies were also searched, which yielded additional relevant studies. There were no restrictions on the publication date to facilitate the collection and identification of all available and relevant articles published before 7 February 2021. We performed a systematic review and meta-analysis according to the PRISMA Statement. This review was registered at PROSPERO and given the identification number CRD42021228461. Results In total, we included 12 randomized controlled trials with 938 subjects. The intervention includes zinc (sulfate, gluconate, picolinate, polaprezinc, and acetate), and the pooled results of the meta-analysis of subjects with idiopathic and zinc-deficient taste disorder indicate that improvements in taste disorder occurred more frequently in the experimental group compared to the control group (RR = 1.38; 95% CI: 1.16, 1.64, p=0.0002). Zinc supplementation appears to confer a greater improvement in taste perception amongst those with chronic renal disease using zinc acetate (overall RR = 26.69, 95% CI = 5.52–129.06, p < 0.0001). The doses are equivalent to 17 mg–86.7 mg of elemental zinc for three to six months. Conclusion Zinc supplementation is an effective treatment for taste disorders in patients with zinc deficiency, idiopathic taste disorders, and in patients with taste disorders induced by chronic renal failure when given in high doses ranging from 68 to 86.7 mg/d for up to six months.


Introduction
Food taste and favour are important elements that afect food choice and acceptance [1]. Disorders of taste can adversely afect patients' health and quality of life [2], resulting in loss of food enjoyment, poor appetite, unintended weight loss, malnutrition, and other psychological and physiological complications [3][4][5]. Taste disorder is characterised by unpleasant tastes, where patients can experience hypogeusia (a condition of reduced ability to taste sweet, sour, bitter, salty, and umami tastes) or ageusia (a total loss of the ability to detect tastes) or dysgeusia (persistent foul, salty, rancid, or metallic taste sensation in the mouth) [6]. Around 200,000 patients visit doctors each year in the US complaining of a change in either taste or smell [1]. In 2003, about 240,000 patients were diagnosed with taste disorders in Japan [2]. A recent US survey using the Chemical Senses Questionnaire (CSQ) reported that the prevalence of taste alteration was 19% in the adult population, with 5% reporting dysgeusia, reaching 27% in elderly populations [7]. More than half of patients (56.9%) in Italy with COVID- 19 have reported a reduction of taste and/or smell; a severe reduction of taste was present in 39.7% of patients [8]. Taste alteration is also observed in 66% of chemotherapy patients [9]. Te most common causes of taste disorder are medications (21.7%), followed by zinc defciency (14.5%), oral and perioral infections, Bell's palsy, oral appliances and age while less common causes include nutritional factors, tumours or lesions associated with taste pathways, head trauma, exposure to toxic chemicals and radiation treatment of the head and neck [10].
Zinc is an important element that supports many functions in humans including the immune system, growth, and development [11]. In addition, zinc is important for the functioning of taste buds [12]. Disturbance of salivary zinc levels has been found to be associated with a decreased level of gustin [13]. Gustin is the major zinccontaining protein in the human parotid saliva [12]; decreases in the secretion of gustin have been linked with abnormalities of the growth and development of the taste buds and the resultant loss of taste [14]. Tis mechanism is supported by numerous studies fnding that patients with hypogeusia had low levels of gustin and salivary zinc [14][15][16] as well as signifcant alterations in the shape of taste buds [15]. Te association between zinc defciency and taste disorders has been well known for years [17][18][19], but evidence for efcacious treatment for taste disorders in clinical practice remains lacking. Although taste disorder has not been given sufcient attention by the medical community and researchers, in recent years, increased interest has emerged in evaluating potential treatments for disorders of taste due to the increasingly recognised adverse efects afecting taste due to bariatric surgery [20] and most recently due to COVID-19 infections [21]. We, therefore, aim to perform a systematic literature review and meta-analysis for available randomized controlled trials to investigate the efcacy of zinc supplementation in the treatment of taste disorders in the adult population.

Methods
We performed our systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [22] to identify the efectiveness of zinc supplementation to prevent and treat taste disorder in patients who had been diagnosed with zinc defciency, idiopathic taste disorder, or taste disorder secondary to chronic renal failure. Included and excluded studies were assessed based on outcomes, participants, intervention types, and study types.

Participants.
All included participants consisted of human populations, and animal studies were excluded. Participant groups consisting of adults ≥18 years were included. We excluded patients who received chemotherapy and radiation, children, and pregnant women. We also excluded patients with taste disorders induced by drug use or taste disorders induced by the common cold.

Intervention.
Te participants received zinc-based therapy for the prevention and treatment of taste disorders compared to controls who received a placebo.

2.1.4.
Outcomes. Improvement of taste disorder in response to zinc treatment was observed in intervention groups compared to the control group at the baseline and during a follow-up period. Zinc levels were also compared before and after treatment. Papers that did not include zinc or taste change outcomes were excluded.

Search Strategy.
A literature search was conducted to describe the efects of zinc supplementation to improve subjective and objective symptoms of taste disorder induced by zinc defciency, idiopathic conditions, or chronic renal failure. Two authors conducted the systematic search in the following electronic bibliographical databases: Ovid MEDLINE, Ovid Embase, Ovid AMAD, and PubMed. Article bibliographies were also searched and yielded additional relevant studies. Tere were no restrictions on publication date, facilitating the collection and identifcation of all available and relevant articles published before 7 February 2021. Te following keywords were used: "taste change," "taste disorder," "taste dysfunction," "dysgeusia," "zinc," "zinc sulphates," and "defciency." Te systematic review was registered at PROSPERO (https://www.crd. york.ac.uk) and given the identifcation number CRD42021228461.

Data Extraction.
We reviewed the articles according to the inclusion and exclusion criteria and summarised the main fndings. Data regarding study duration, sample size, methods of detection of taste disorder, zinc dose, treatment period, and outcomes were extracted and are summarised in Tables 1 and 2. All the data those were utilised for the metaanalysis component were dichotomous data to fnd out the number of events in both the intervention and placebo groups. Additionally, all zinc supplement doses were considered for meta-analysis implementation.

Assessment of the Risk of Bias in Selected Studies.
We used the Cochrane quality assessment tool to the assessed risk of bias for randomized controlled trials. Te Cochrane tool, as described in the Handbook for Systematic Reviews of Interventions, evaluates the following attributes: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other forms of bias. Rating criteria include low risk of bias, high risk of bias, or unclear risk of bias [35]. Te Cochrane risk-of-bias tool for randomized trials (RoB) was independently performed by two investigators (BM and HM).

Statistical Procedures.
Te meta-analysis was conducted using Review Manager 5. Te Mantel-Haenszel (M-H) statistical method was selected with the random efect method for dichotomous data and established the outcome measure as a total and event based on Cochrane recommendation. All pooled results were reported as relative risk (RR) and 95% confdence intervals (CI) for all individual studies, in addition to an efect size estimate (Z-statistic) and a measure of statistical signifcance (p < 0.05). To distinguish between the observed efects of zinc supplementation in iatrogenic or primary zinc defciency versus chronic renal disease, two separate forest plots were generated for each. Further, data points from all studies at the synthesis stage were included, where data pertaining to event and total count, the equivalent quantity of elemental zinc, and the pharmaceutical name of the zinc supplement are stated. Finally, subanalysis was performed, based on the pharmaceutical name of the zinc supplement (s) included at the quantitative synthesis stage.
2.6. Assessment of Heterogeneity. We followed the Cochrane Handbook for Systematic Review of Interventions guidelines to assess the heterogeneity of the studies that were generated through the associated forest plots using Review Manager 5.

Summarizing and Interpreting
Results. Review Manager 5 was used to conduct the meta-analysis, the risk-of-bias assessment, and the summary of the fndings in Table 3 for each outcome included in this review. We imported the data to GRADEpro software to assess the evidence for each outcome. GRADE was also used to assess the quality of reported results in Table 4. We did not perform an analysis for publication bias via funnel plot as there were less than 10 studies included in the meta-analysis. Tis is because when there are fewer studies the power of the tests is too low to distinguish the chance from real asymmetry and in this study the largest forest plot only had seven data points across four studies.

Study Selection.
A fow diagram of our literature search is shown in Figure 1. Following exclusions and removals, complete data extraction was performed on a total of 12 articles that met the inclusion criteria. Of these studies, four were included in a qualitative synthesis, and eight were included in a quantitative synthesis (meta-analysis) [36]. Te characteristics of these 12 articles are shown in Table 1.

Trial Settings.
Twelve randomized controlled trials (RCTs) are included in this review; all but one was written in English. One was in Japanese but was translated to English (Ikeda et al. [23]) Te most common countries of origin of these studies were Japan and the US; one was from the UK, and one was from Germany. Out of 12 trials, 2 were crossover trials.

Study Populations.
A total of 938 subjects were included in this study, all adults. Te minimum age included in the trials was 18 years or older and the highest age observed was 84 years old; the lowest sample size was 22 and the highest sample size was 219. Eight studies included both genders in their trials; one study included only males and three trials did not report gender distribution. Four studies were on idiopathic taste disorder, three concerned idiopathic and zinc-defcient taste disorder, and fve were on renal failure-induced taste disorder.

Risk of Bias in Included Studies.
Most studies were found to have an unclear risk of bias. However, four studies have a high risk of bias and three studies have a low risk of bias.
(2) Zinc Gluconate. Tree trials studied the efcacy of zinc gluconate supplementation in idiopathic and zinc-defcient taste disorders. Yoshida et al. [29] administered 158 mg of Te risk in the intervention group (and its 95% confdence interval) is based on the assumed risk in the comparison group and the relative efect of the intervention (and its 95% CI). CI: confdence interval; RR: risk ratio. GRADE working group grades of evidence. High certainty: We are very confdent that the true efect lies close to that of the estimate of the efect. Moderate certainty: We are moderately confdent in the efect estimate. Te true efect is likely to be close to the estimate of the efect, but there is a possibility that it is substantially diferent. Low certainty: Our confdence in the efect estimate is limited. Te true efect may be substantially diferent from the estimate of the efect. Very low certainty: We have very little confdence in the efect estimate. Te true efect is likely to be substantially diferent from the estimate of efect. a: some concern with random sequence generation and lack of follow-up; b: wide confdence intervals in Heckmann et al. [26]; c: some concern of lack of follow-up; d: very wide confdence intervals in all three included trials.
zinc gluconate (equivalent to 22.59 mg/d of elemental zinc) for four months at a high risk of bias. Heckmann et al. [26] administered 140 mg (equivalent to 20 mg of elemental zinc) for three months at low risk of bias. An improvement in taste disorder was observed for the zinc supplement groups (RR 1.61, 95% CI: 1.12-2.31, p � 0.01) among 102 participants ( Figure 2).
Stewart-Knox et al. [25] administered zinc gluconate equivalent to 15 or 30 mg of elemental zinc per day over six months and were at high risk of bias. Te study showed that zinc level increased postintervention in both groups and were greater in the 30 mg supplemented group; acuity for salt taste was greater in the 30 mg supplemented group (p � 0.031) while 15 and 30 mg Zn  groups did not improve any tastes acuity. However, we could not conduct a meta-analysis of the results because the study did not report the number of events in the placebo group.
(3) Zinc Picolinate. Of the studies included, only one [28] was found to examine the efcacy of zinc picolinate on taste disorder patients at a high risk of bias. An improvement in taste disorder at a dosage of 28.9 mg three times/d for three months (RR 1.70, 95% CI: 1.13-2.56, p � 0.01) (Figure 2), with 73 participants.
(4) Zinc Sulphate. In 1976, Henkin et al. [34] examined the efectiveness of four doses of 100 mg of zinc ion, with an unclear risk of bias. Te results from this study indicated that both placebo and treatments groups with zinc sulfate showed equivalent improvements. We excluded this study from the meta-analysis because number of events in both the intervention and placebo groups was unclear.

Zinc Disorder Secondary to Chronic Renal Failure
(1) Zinc Acetate. Zinc acetate was used as a treatment for taste disorder induced by chronic renal failure in three studies [30][31][32]. Each study provided a single data point each, with the overall RR for zinc acetate found to be 26.69 (95% CI � 5.52-129.06, p < 0.0001) (Figure 3). Te total number of participants in the three studies was 77 patients. A heterogeneity assessment was inconclusive (I 2 � 0%, p � 0.98) (Figure 3).
(2) Zinc Sulphate. Two studies, Atkin-Tor et al. [33] and Matson et al. [27], examined the efcacy of zinc sulfate in taste disorder induced by chronic renal failure for up to  Figure 2: Meta-analysis of the efect of zinc replacement for the treatment of taste disorder. Forest plot including data analysis of fve studies with a total of 508 cases of idiopathic and zinc-defcient taste disorder enrolled to experimental (n � 259) and control groups (n � 249). Data expressed as event "total number of cases that improved after receiving the treatment or placebo," and total "total number of participants in either control or experimental group" p value for heterogeneity was 0.22. Te pooled results of this meta-analysis indicated that taste disorder improvement occurred signifcantly more frequently in the supplemented group compared to the control group. Overall RR is positive (RR � 1.38, 95% CI � 1.16-1.64), and statistical signifcance was found to be p � 0.0002. a six-week intervention period. In a double-blind crossover trial, Atkin-Tor et al. [33] introduced 440 mg of zinc sulfate three times per week at a high risk of bias, the results of this study showed a signifcant improvement in taste acuity in the supplemented group. Whereas Matson introduced 220 mg of zinc sulphate per day at an unclear risk of bias, the results from this study showed no improvements in both the intervention and placebo groups. Tese two trials did not provide sufcient details about the placebo groups. We have therefore excluded them from the meta-analysis.

Discussion
Tis systematic review assessed the efcacy of zinc supplementation to improve taste disorders. We focused on the outcomes of intervention groups compared to placebo among patients with zinc defciency and idiopathic taste disorder or taste disorder induced by chronic renal failure. We included 12 randomized controlled trials: four were included in a qualitative synthesis and eight in a metaanalysis. We assessed fve studies as having an unclear risk of bias [23,24,27,32,34], four studies at a high risk of bias [25,28,29,33], and three studies at low risk of bias [26,30,31]. Seven included studies examined the efectiveness of diferent zinc supplementations (polapre zinc, picolinate, zinc gluconate, and zinc sulphate) among patients with zinc defciency and idiopathic taste disorder. We did not include two studies such as the study by Henkin et al. [34] and Stewart-Knox et al. [25] in the meta-analysis because of their unclear methodologies and unreported data for the placebo groups. Out of seven studies that examined the efcacy of zinc supplementation in taste disorders induced by chronic renal failure, we did not include Atkin-Tor et al. [33] and Matson et al. [27] in the meta-analysis because they did not report data about the placebo groups.

Summary of Main Results.
Te pooled results of this meta-analysis indicated that improvement in taste disorder occurred signifcantly more frequently in the intervention group compared to the control group. Tere was a signifcant improvement in taste following zinc supplementation at the study level except in three studies [24,26,29]. Te improvement in taste following zinc supplementation was observed at the meta-analysis level. We found that zinc supplements reduced the risk of taste disorder by 51%. Moreover, the pooled results of the largest studies [23,24,28] indicated that zinc supplementation is an effective treatment for taste disorders in patients with zinc defciency or idiopathic taste disorders when given in high doses ranging from 68 to 86.7 mg/d for up to three months. Tis results in agreement with Yagi et al.'s [37] review which indicated that zinc supplementation contributes to the treatment of taste disorders caused by zinc defciency. In contrast, Kumbargere Nagraj et al. [38] did not fnd sufcient trials to support the efectiveness of zinc in taste disorder improvement. Te level of included studies ranged from moderate to high using Te Grading of Recommendations Assessment, Development and Evaluation (GRADE). Heckmann et al. [26] and Yoshida et al. [29] introduced a low dose of elemental zinc, around 20-22.59 mg/d, for up to three to four months to patients with taste disorders induced by zinc defciency or idiopathic disease and our meta-analysis showed insignifcant improvement of taste disorders, however, the results for these two trials should be viewed with caution due the quality of evidence was rated as low, and high risk of bias for one study Yoshida et al. [29].
In the three studies concerning taste disorder induced by chronic renal failure, we found the level of evidence and its quality to be low. Tis was driven by the fact that the studies mainly had small sample size and the absence of event numbers in the placebo group, which resulted in a high upper limit of the CI [30][31][32] in the meta-analysis. Overall, per the available data, zinc supplementation appears to confer a greater improvement in taste perception amongst those with chronic renal disease using zinc acetate (overall RR � 26.69, 95% CI � 5.52-129.06, p < 0.0001) (Figure 3) in comparison to the extent of improvement using alternative supplements in the iatrogenic or zinc defciency disease groups ( Figure 2 Figure 3: Meta-analysis of the efect of zinc replacement for taste disorder in patients with chronic renal failure. Forest plot including data analysis of three studies with a total of 77 cases of taste disorder induced by chronic renal failure, enrolled to experimental (n � 34) and control groups (n � 43). Data expressed as event "total number of cases that improved after receiving the treatment or placebo" and total "total number of participants in either control or experimental group" p value for heterogeneity was 0.98. Te pooled results of this metaanalysis indicated that taste disorder improvement occurred signifcantly more frequently in the supplemented group compared to the control group. Overall RR is positive (RR � 26.69, 95% CI � 5.52-129.06), and statistical signifcance was found to be p < 0.0001. response to zinc acetate between the chronic renal disease and iatrogenic or zinc defciency cohorts was not possible due to missing data. Furthermore, zinc picolinate was represented by a single data point [28]. In all studies included in this meta-analysis, we did not fnd considerable statistical heterogeneity. Nevertheless, there is substantial heterogeneity based on elemental zinc-equivalent dose, supplement chemical structure, follow-up time, and disease state exists, as inferred based on the study characteristics as we aimed to collect all available RCTs to examine the effectiveness of zinc supplementation in taste disorder treatment. We suggest that zinc supplementation may improve specifc tastes more than others depending on the case or the disease-induced taste disorder. We suggest a high dose of elemental zinc 68-86.7 mg/d for up to six months to improve taste disorders. However, the results of this metaanalysis should be interpreted with caution as excessive zinc supplementation might have serious health outcomes and toxicity when taken at a signifcantly higher than the Recommended Dietary Allowance (RDA) (100-300 mg/day vs. 15 mg daily). It has been proposed that even smaller doses of zinc supplementation, closer to the RDA, interfere with the utilisation of copper and iron and negatively impact HDL cholesterol levels. Zinc supplement users should be informed of any potential risks associated with its usage [39].

Strengths and Limitations of Tis Study.
Unlike other reviews in this area, our systematic review provided additional evidence and clarifcation of zinc supplementation's efcacy in improving taste disorder in adult populations by stratifying according to zinc dose, formulation type, and treatment duration. However, one aspect that can limit the analysis and discussion of the results is the heterogeneity of the methods used. Te studies assessed combined objective outcomes (e.g., flter paper disk; detection and recognition thresholds for sweet, sour, salty, bitter, and umami tastes) and subjective outcomes (e.g., questionnaires results). However, whether the diference between subjective and objective methods could signifcantly afect the results of improvement is unclear. In another review, the author examined the overall improvement in taste acuity using both subjective and objective methods; however, the author could not conclude the overall efect because of the very low level of evidence. High-quality research is required to compare diferent objective and subjective methods [38]. We observed that some studies detected taste improvement in only one type of taste, so a further limitation of our metaanalysis is that we defned "improvement" as an improvement of any of the fve basic tastes: sweet, sour, bitter, salty, and umami tastes.

Conclusion
High-dose zinc supplementation is an efective treatment for taste disorders in patients with zinc defciency or idiopathic taste disorder and in patients with taste disorders induced by chronic renal failure.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon reasonable request.

Disclosure
Te views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. A previous version of this study has been submitted as an abstract as a conference paper https:// publications.waset.org/abstracts/148658/pdf.

Conflicts of Interest
Te authors declare that there are no conficts of interest.